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Hox genes and their cofactors are essential developmental genes that specify regional identity in animals, including insects. A particularly interesting feature of Hox genes is their conserved arrangement in clusters in the same order in which they specify identity along the anterior-posterior axis. Among insects, breaks in the cluster have been reported in a few species, but these seem to be the exception rather than the rule. We have annotated the ten Hox genes of the Asian citrus psyllid, Diaphorina citri, and determined that there is a split in its Hox cluster between the Deformed and Sex combs reduced genes. This is the first time a break at this position has been observed in an insect Hox cluster. We have also annotated the D. citri orthologs of the Hox cofactor genes homothorax, PKNOX and extradenticle. Interestingly, we found an additional copy of extradenticle in D. citri that appears to be a retrogene. Expression data and sequence conservation suggest that the extradenticle retrogene may have retained the original extradenticle function and allowed the parental extradenticle gene to diverge.

A massive adaptive radiation on the Hawaiian archipelago has produced approximately one quarter of the fly species in the family Drosophilidae. The Hawaiian Drosophila clade has long been recognized as a model system for the study of both the ecology of island endemics and the evolution of developmental mechanisms, but relatively few genomic and transcriptomic datasets are available for this group. We present here a differential expression analysis of the transcriptional profiles of two highly conserved embryonic stages in the Hawaiian picture-wing fly Drosophila grimshawi. When we compared our results to previously published datasets across the family Drosophilidae, we identified cases of both gains and losses of gene representation in D. grimshawi, including an apparent delay in Hox gene activation. We also found high expression of unannotated genes. Most transcripts of unannotated genes with open reading frames do not have homologs in non-Hawaiian Drosophila species, although the vast majority have sequence matches in other genomes of the Hawaiian picture-wing flies. Some of these genes may have arisen from non-coding sequence in the ancestor of Hawaiian flies or during the evolution of the clade. Our results suggests that both the modified use of ancestral genes and the evolution of new ones may occur in rapid radiations.RESEARCH HIGHLIGHTSThe early embryonic transcriptome of the Hawaiian fly Drosophila grimshawi shows a loss of expression of conserved Stage 5 genes, including the Hox genesThe de novo evolution of embryonically expressed genes may be occurring in the Hawaiian Drosophila lineageAUTHORS’ STATEMENTThis paper is not being considered for publication elsewhere. This study formed part of Madeline Chenevert’s M.S. thesis.

In order to explore effects of long-chain non-coding ribonucleic acid (RNA) HOTAIR on proliferation and migration of human lens epithelial cells, SRA01/04 cells were selected as the research strain in this study and divided into S1 group (no HOTAIR transfection), S2 group (siHOTAIR transfection), S3 group (siHOTAIR+10 ng/mL TGF-β2), and S4 group (no HOTAIR transfection+10 ng/mL TGF-β2) according to the presence or absence of transforming growth factor (TGF)-β2 and silent HOTAIR treatment. 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) colorimetric method was applied to detect cell proliferation.Western blot was used for detection of E-cadherin, zonula occluden-1 (ZO-1), Vimentin, α-smooth muscle actin (SMA), Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), and Smad-2 expressions. Results showed that the number of transmembrane cells in S4 group was higher markedly than that of the other groups, but that of S2 group dropped steeply compared with the other groups (P α-SMA (0.64±0.28) decreased sharply compared with the other groups (P < 0.05); Snail (2.51±0.59), Slug (2.11±0.47), and ZEB1 (2.83±0.53) of S4 group rose obviously compared with the other groups, but the above of S2 group reduced hugely compared with the other groups (P < 0.05); pSmad-2 and pSmad-3 of S4 group elevated greatly compared with the other groups, and those of S2 group reduced hugely compared with the other groups (P < 0.05). In conclusion, HOTAIR high expression could promote TGF-β2-induced SRA01/04 cell proliferation, migration, invasion, and epithelial-mesenchymal trans-differentiation, which was related to TGF-β/Smad signaling pathway.

Aims: HOX clusters encode proteins that play pivotal roles in regulating transcription factors and many other proteins during embryogenesis. However, little is known about the diagnostic and prognostic values of HOXC family members in gastric cancer (GC). Materials and methods: The authors evaluated the data in patients with GC based on bioinformatics analysis. Results: HOXC6/8/9/10/11/13 were overexpressed in GC and associated with a poor prognosis. HOXC4/5 were downregulated in GC tissues. Receiver operating characteristic curve analysis demonstrated that they have high diagnostic value. In addition, HOXC4/5/6/9/10/11/13 were negatively correlated with DNA methylation level. The gene set enrichment analysis results implied that they play essential roles in multiple biological processes underlying tumorigenesis. Conclusion: HOXC family members are potential targets for diagnosis and may work as prognostic biomarkers of GC.

MicroRNAs (miRNAs) may modulate more than 60% of human coding genes and act as negative regulators, while long non-coding RNAs (lncRNAs) regulate gene expression on multiple levels by interacting with chromatin, functional proteins, and RNAs such as mRNAs and microRNAs. However, the crosstalk between lncRNA HOTTIP and miRNAs in leukemogenesis remains elusive. Using combined integrated analyses of global miRNA expression profiling and state-of-the-art genomic analyses of chromatin such as ChIRP-seq., (genome wide HOTTIP binding analysis), ChIP-seq., and ATAC-seq., we found that miRNA genes are directly controlled by HOTTIP. Specifically, the HOX cluster miRNAs (miR-196a, miR-196b, miR-10a and miR-10b), located cis & trans, were most dramatically regulated and significantly decreased in HOTTIP-/- AML cells. HOTTIP bound to the miR-196b promoter, and HOTTIP deletion reduced chromatin accessibility and enrichment of active histone modifications at HOX cluster associated miRNAs in AML cells, while reactivation of HOTTIP restored miR gene expression and chromatin accessibility in the CTCF-boundary-attenuated AML cells. Inactivation of HOTTIP or miR-196b promotes apoptosis by altering the chromatin signature at the FAS promoter and increasing FAS expression. Transplantation of miR-196b knockdown MOLM13 cells in NSG mice increased overall survival compared to wild-type cells. Thus, HOTTIP remodels the chromatin architecture around miRNAs to promote their transcription, consequently repressing tumor suppressors and promoting leukemogenesis.

The surprising variation in the number of Hox clusters and genome structure in ray-finned fish lineages reflects the history of duplications and subsequent lineage-specific gene loss. However, there are few studies on whether Hox clusters in the early generations of hybrid lineages show more significant variation due to the continuous genomic oscillation caused by distant hybridization. We sequenced and analyzed Hox gene clusters from a crucian carp-like homodiploid fish (NCRC) lineage (a new hybrid lineage derived from common carp (Cyprinus carpio) (♀) ​× ​blunt snout bream (Megalobrama amblycephala) (♂)). In the NCRC lineage, we reconstructed seven Hox clusters consisting of 48 Hox genes, ten of which were pseudogenes. The number of putative Hox clusters generated in NCRC-F1 was increased greatly by distant hybridization to an average number almost twice that in the maternal parent. This increasing trend continued in the subsequent self-mating generations of NCRC-F1. In contrast, the number of Hox cluster fragments inherited from the original parents gradually decreased as the number of NCRC lineage generations increased. This pattern was also found in the inheritance of recombinant Hox clusters. In terms of base composition, some genetic rules for the inheritance of these Hox clusters between different generations of the NCRC lineage were identified. Furthermore, the newly derived mutated Hox clusters in the NCRC lineage showed phylogenetic relationships that were closer to either crucian carp or silver crucian carp, revealing a clear evolutionary path. This study deepens our understanding of the evolution of Hox genes in the ray-finned fish clade.

The essential role HOX-associated non-coding RNAs play in chromatin dynamics and gene regulation has been well documented. The potential roles of these microRNAs and long non-coding RNAs in oral cancer development, with their attendant involvement in various cellular processes including proliferation, invasion, migration, epithelial-mesenchymal transition and metastasis is gaining credence. An interaction network of HOX-embedded non-coding RNAs was constructed to identify the RNA interaction landscape using the arena-Idb platform and visualized using Cytoscape. The miR-10a was shown to interact with HOXA1, miR-10b with HOXD10, miR-196a1 with HOXA5, HOXA7, HOXB8, HOXC8, HOXD8, and miR-196a2 with HOXA5. The lncRNAs, HOTAIR interacted with HOXC11, HOTAIRM1 with HOXA1 and HOXA4, HOTTIP with HOXA13, HOXA-AS2 with HOXA3, HOXA11-AS with HOXA11 and HOXD-AS1 with HOXB8. Changes in the HOX cluster-embedded non-coding RNAs have implications for prognosis and overall disease survival. Our review aims to analyze the functional significance and clinical relevance of non-coding RNAs within the HOX cluster in the context of oral carcinogenesis. Elucidating these interactions between the non-coding RNAs and HOX genes in oral cancer development and progression could pave the way for the identification of reliable biomarkers and potential therapeutic targets.

HOX genes belong to the highly conserved homeobox superfamily, responsible for the regulation of various cellular processes that control cell homeostasis, from embryogenesis to carcinogenesis. The abnormal expression of HOX genes is observed in various cancers, including breast cancer, where they act as oncogenes or as suppressors of cancer, according to context. In this review, we analyze HOX gene expression patterns in breast cancer and examine their relationship, based on the three-dimensional genome structure of the HOX locus. The presence of non-coding RNAs embedded within the HOX cluster and the role of these molecules in breast cancer, have been reviewed. We further evaluate the characteristic activity of HOX protein in breast cancer and its therapeutic potential.

Set-nup214 is a recurrent fusion gene that is mainly observed in T-cell acute lymphoblastic leukemia (T-ALL). Dysregulation of homeobox (Hox) genes is frequently observed in patients with leukemia. Consistent with this, HoxA genes are upregulated in the set-nup214 + T-ALL cell line and patients. Although SET-Nup214 has been reported to be recruited to the promoter regions of HoxA genes, the detailed mechanisms of how SET-Nup214 specifically binds to HoxA gene promoters and regulates HoxA gene expression are not known. In this study, we demonstrated that SET-Nup214 interacts with MLL via the SET acidic region of SET-Nup214. SET-Nup214 and MLL cooperatively enhance the promoter activity of the HoxA10 gene. Neither the SET region alone nor the Nup214 region alone sufficiently enhanced the HoxA10 gene promoter. Our results indicated that the SET portion of the SET-Nup214 fusion protein is important for interactions with MLL and transcription enhancement of the HoxA10 gene. Thus, our study will contribute to the understanding of how SET-Nup214 and MLL disturb the expression of HoxA10 gene in leukemia.

The three-dimensional (3D) organization of the genome is highly dynamic, changing during development and varying across different tissues and cell types. Recent studies indicate that these changes alter regulatory interactions, leading to changes in gene expression. Despite its importance, the mechanisms that influence genomic organization remain poorly understood. We have previously identified a network of chromatin boundary elements, or insulators, in the Drosophila Antennapedia homeotic complex (ANT-C). These genomic elements interact with one another to tether chromatin loops that could block or promote enhancer-promoter interactions. To understand the function of these insulators, we assessed their interactions by measuring their 3D nuclear distance in developing animal tissues. Our data suggest that the ANT-C Hox complex might be in a folded or looped configuration rather than in a random or extended form. The architecture of the ANT-C complex, as read out by the pair-wise distance between insulators, undergoes a strong compression during late embryogenesis, coinciding with the reduction of cell and nuclear diameters due to continued cell divisions in post-cleavage cells. Our results suggest that genomic architecture and gene regulation may be influenced by cellular morphology and movement during development.

Female fertility in mammals requires iterative remodeling of the entire adult female reproductive tract across the menstrual/estrous cycle. However, while transcriptome dynamics across the estrous cycle have been reported in human and bovine models, no global analysis of gene expression across the estrous cycle has yet been reported for the mouse. Here, we examined the cellular composition and global transcriptional dynamics of the mouse oviduct along the anteroposterior axis and across the estrous cycle. We observed robust patterns of differential gene expression along the anteroposterior axis, but we found surprisingly few changes in gene expression across the estrous cycle. Notable gene expression differences along the anteroposterior axis included a surprising enrichment for genes related to embryonic development, such as Hox and Wnt genes. The relatively stable transcriptional dynamics across the estrous cycle differ markedly from other mammals, leading us to speculate that this is an evolutionarily derived state that may reflect the extremely rapid five-day mouse estrous cycle. This dataset fills a critical gap by providing an important genomic resource for a highly tractable genetic model of mammalian female reproduction.

Objective The objective of this study was identification of the transcription factor binding sites (TFBS) in the promoter of HOX genes and elucidation of the comprehensive interaction of transcription factors (TFs)/genes with HOX. Methodology Promoter sequences of HOXA3, HOXA5, HOXA9, HOXA10, HOXA13, HOXB5, HOXC10, HOXC12, and HOXD10 were analyzed to predict the TFBS and their targets using TRANSFAC, TRRUST, and Harmonizome. Functional analysis of the processed data sets was carried out using DAVID and GATHER gene annotation tools. A network of regulatory interactions was constructed using NetworkAnalyst and a comprehensive illustration of the TF-gene network was constructed with HOX as a central hub using the Encyclopedia of DNA Elements chromatin immunoprecipitation sequencing data. Further, the enriched network was constructed to elucidate the roles of these genes in the various pathways. Results Binding sites for E2F1, HNF3α, SP3, and KLF6 were common to promoter regions of all of the HOX genes. The functional annotation and pathway analysis elucidated the regulatory activity of a distinct set of TF-genes in interaction with HOX. A P value ≤.05 and false discovery rate ≤0.01 were considered statistically significant. Conclusion We have confirmed that the predicted TFBSs in the HOX gene promoters function in transcriptional regulation by modulating target gene activity. TF-gene interactions are crucial to understanding oral carcinogenesis.

Hoxa2 genes provide critical patterning signals during development, and their regulation and function have been extensively studied. We report a previously uncharacterized significant sequence divergence of a highly conserved hindbrain hoxa2b enhancer element in the family syngnathidae (pipefishes, seahorses, pipehorses, seadragons). We compared the hox cis-regulatory element variation in the Gulf pipefish and two species of seahorse against eight other species of fish, as well as human and mouse. We annotated the hoxa2b enhancer element binding sites across three species of seahorse, four species of pipefish, and one species of ghost pipefish. Finally, we performed in situ hybridization analysis of hoxa2b expression in Gulf pipefish embryos. We found that all syngnathid fish examined share a modified rhombomere 4 hoxa2b enhancer element, despite the fact that this element has been found to be highly conserved across all vertebrates examined previously. Binding element sequence motifs and spacing between binding elements have been modified for the hoxa2b enhancer in several species of pipefish and seahorse, and that the loss of the Prep/Meis binding site and further space shortening happened after ghost pipefish split from the rest of the syngnathid clade. We showed that expression of this gene in rhombomere 4 is lower relative to the surrounding rhombomeres in developing Gulf pipefish embryos, reflecting previously published functional tests for this enhancer. Our findings highlight the benefits of studying highly derived, diverse taxa for understanding of gene regulatory evolution and support the hypothesis that natural mutations can occur in deeply conserved pathways in ways potentially related to phenotypic diversity.

The genes TLX 1 and TLX 3 as two genes of the Hox gene family have been selected in this review. Such genes have been shown to have a certain function in malignancies, including acute lymphoblastic T cell leukaemia (T-ALL). The principal phases of the research involved extraction of DNA as well as gene sequence of normal and ill cases. This thesis included partial examination of the above two genes in T-cell Both patients for adults and infants. Further analyses were performed using bioinformatic tools to establish the variation in the secondary structure of mRNA. The key knowledge was obtained that the proposed protein products had physicochemical properties in relation to the secondary structure of mRNA. Finally, the variation in samples compared with standard controls will influence the stability of these protein products. This knowledge will serve both as a disease detector and in connection to patients with a relapse.

Summary How transcription factors regulate a distinct set of target genes in different cell types is a fundamental question. A new study demonstrates how Ultrabithorax, a Hox transcription factor, acts as both a repressor and an activator in a cell type-specific manner to alter chromatin accessibility and gene regulation.

This article also appears in: Evolution 2021, Evolution 2021 Virtual Issue., The acquisition of wings has facilitated the massive evolutionary success of pterygotes (winged insects), which now make up nearly three-quarters of described metazoans. However, our understanding of how this crucial structure has evolved remains quite elusive. Historically, two ideas have dominated in the wing origin debate, one placing the origin in the dorsal body wall (tergum) and the other in the lateral pleural plates and the branching structures associated with these plates. Through studying wing-related tissues in the wingless segments (such as wing serial homologs) of the beetle, Tribolium castaneum, we obtained several crucial pieces of evidence that support a third idea, the dual origin hypothesis, which proposes that wings evolved from a combination of tergal and pleural tissues. Here, we extended our analysis outside of the beetle lineage and sought to identify wing-related tissues from the wingless segments of the cockroach, Blattella germanica. Through detailed functional and expression analyses for a critical wing gene, vestigial (vg), along with re-evaluating the homeotic transformation of a wingless segment induced by an improved RNA interference protocol, we demonstrate that B. germanica possesses two distinct tissues in their wingless segments, one with tergal and one with pleural nature, that might be evolutionarily related to wings. This outcome appears to parallel the reports from other insects, which may further support a dual origin of insect wings. However, we also identified a vg-independent tissue that contributes to wing formation upon homeotic transformation, as well as vg-dependent tissues that do not appear to participate in wing formation, in B. germanica, indicating a more complex evolutionary history of the tissues that contributed to the emergence of insect wings., This study is supported by the Miami University Faculty Research Grants Program (CFR; to Yoshinori Tomoyasu), the National Science Foundation (NSF; IOS1557936 to Yoshinori Tomoyasu), an NSF Graduate Research Fellowship (to Courtney Clark-Hachtel), the Spanish Ministry of Economy and Competitiveness (including support for the visit of Ana Fernandez-Nicolas to the Tomoyasu lab; CGL2012-36251, CGL2015-64727-P, and PID2019-104483GB-I00 to Xavier Belles), the Catalan Government (2014 SGR 619, 2017 SGR 10c0 to Xavier Belles), and European Fund for Economic and Regional Development (FEDER funds to Xavier Belles).

HOX transcript antisense intergenic RNA (HOTAIR) is a lncRNA with a length of 2,158 nucleotides and its two terminal domains could combine with different complexes to function at the level of transcription and translation. It overexpresses in many cancers including gastric cancer. HOTAIR could play an oncogenic role in the initiation and progression of gastric cancer through interaction with microRNAs, such as miR-330/618/126 in the PI3K/Akt signaling pathways. HOTAIR single nucleotide polymorphisms (SNPs) may have genotype-function and allele-specific effect on gastric cancer by a mechanism that specific SNP could give rise to a variation of HOTAIR and alter the binding site of microRNAs. Both rs920778 T allele and rs4759314 G allele will enhance the susceptibility to gastric cancer in the Chinese populations. In a word, the suppression of HOTAIR and overexpression of downstream microRNAs may be potential therapeutic strategies of gastric cancer related to HOTAIR.

Background To investigate the effects of long non-coding RNA HOX transcript antisense intergenic RNA (lncHOTAIR) on the proliferation and migration of Tca-8113 cells and TSCCA cells, as well as the epithelial-mesenchymal transition (EMT), and Notch signaling pathway. To further explore the role of HOTAIR in the development of tongue cancer. Methods Transfection was performed on Tca8113 cells using siRNA to knock down the expression of HOTAIR. 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazole-2, 5-diphenyltetrazole-2, bromination method (MTT) was used to determine the proliferation of the experimental group and the control group. And cellular migration and invasion was evaluated using Transwell assay. Western blot analysis was performed to determine the EMT related protein expression, together with the Notch signaling pathway related protein such as Jagged-1, Notch-1, and Hes-1. Results The proliferation of cancer cells was inhibited after silencing with small interfering (si)RNA. The invasion and migration of cancer cells was inhibited after silencing with small interfering (si)RNA (P

Mounting evidence shows that long noncoding RNAs play important roles in human diseases and radioresistance could be an important factor for tumor recurrence. We observed that HOX antisense interge...

Sexual dimorphism in the ratio of digits length is a morphological feature resulted from the interaction between sex hormones and prenatal Hox genes, the latter is known to control the development of both limbs and genitals. The status of this trend and ratios have been investigated in various animal groups, including humans, other mammals, birds, reptiles, and amphibians. In this study, the body length and sexual dimorphism in the second-to-fourth, second-to-third and third-to-fourth digit lengths ratios (i.e., 2D:3D, 2D:4D, 3D:4D) of left fore and hind limbs were investigated in 54 specimens of toads collected from the northern Iran, including Bufo viridis (16 males and 19 females) and Pelobates syriacus (10 males and 9 females). In addition, the body length of the studied specimens were recorded. The results showed that the average body length (SVL) of female individuals of Pelobates syriacus was higher than those in males, which was found to be statistically significant (P≤0.05). Meanwhile, the average body length (SVL) of female individuals of Bufo viridis was found to be higher than those in males, however, the difference was not statistically significant. No sexual dimorphism was detected in the second-to-fourth, second-to-third and third-to-fourth digit lengths ratios of left fore and hind limbs between the male and female undividuals of Bufo viridis. However, the second-to-fourth digit ratio (2D:4D) in Pelobates syriacus species were found to be significantly different (P=0.040) between the male and female individuals, as the ratio was higher in males than females. Therefore, it could be concluded that the sexual dimorphism in 2D:4D of Pelobates syriacus species is consistent with those in most amphibians and diapsids.

Both HOX gene expression and CTCF regulation have been well demonstrated to play a critical role in regulating maintenance of leukemic stem cells (LSCs) that are known to be resistant to BET inhibitor (BETi). To investigate the regulatory role of CTCF boundary in aberrant HOX gene expression and the therapeutic sensitivity of BETi in AML, we employed CRISPR-Cas9 genome editing technology to delete 47 base pairs of the CTCF binding motif which is located between HOXA7 and HOXA9 genes (CBS7/9) in different subtypes of AML with either MLL-rearrangement or NPM1 mutation. Our results revealed that HOXA9 is significantly downregulated in response to the CBS7/9 deletion. Moreover, CBS7/9 boundary deletion sensitized the BETi treatment reaction in both MOLM-13 and OCI-AML3 cells. To further examine whether BETi therapeutic sensitivity in AML is depended on the expression level of the HOXA9 gene, we overexpressed the HOXA9 in the CBS7/9 deleted AML cell lines, which can rescue and restore the resistance to BETi treatment of the CBS7/9 KO cells by activating MAPK signaling pathway. Deletion of CBS7/9 specifically decreased the recruitment of BRD4 and RNA pol II to the posterior HOXA genes, in which, a transcription elongation factor ELL3 is the key factor in regulating HOXA gene transcription monitored by CBS7/9 chromatin boundary. Thus, disruption of CBS7/9 boundary perturbs HOXA9 transcription and regulates BETi sensitivity in AML treatment. Moreover, alteration of CTCF boundaries in the oncogene loci may provide a novel strategy to overcome the drug resistance of LSCs. Graphical abstract.

Wing polymorphism significantly contributes to the ecological success of some insect species. For example, the brown planthopper (BPH) Nilaparvata lugens, which is one of the most destructive rice pests in Asia, can develop into either highly mobile long-winged or highly fecund short-winged adult morphs. A recent study reported a highly provocative result that the Hox gene Ultrabithorax (Ubx) is expressed in BPH forewings and showed that this wing development gene is differentially expressed in nymphs that develop into long-winged versus short-winged morphs. Here, we found that Ubx may be a mir-9a target, and used dual luciferase reporter assays and injected micro RNA (miRNA) mimics and inhibitors to confirm the interactions between mir-9a and NlUbx. We measured the mir-9a and NlUbx expression profiles in nymphs and found that the expression of these two biomolecules was negatively correlated. By rearing BPH nymphs on host rice plants with different nutritional status, we were able to characterize a regulatory cascade between insulin receptor genes, mir-9a, and NlUbx that regulate wing length in BPHs. When host quality was low, NlInR1 expression in the nymph terga increased and NlInR2 expression decreased; this led to a higher mir-9a level, which in turn reduced the NlUbx transcript level and ultimately resulted in longer wing lengths. Beyond extending our understanding of the interplay between host plant status and genetic events that modulate polymorphism, we demonstrated both the upstream signal and miRNA-based regulatory mechanism that control Ubx expression in BPH forewings.

Ependymomas are a heterogeneous group of central nervous system tumors. Despite the recent advances, there are no specific biomarkers for ependymomas. In this study, we explored the role of homeobox (HOX) genes and long noncoding RNA (LncRNA) HOTAIR in ependymomas along the neural axis. Bioinformatics analysis was performed on publicly available gene expression data. Quantitative RT-PCR was used to determine the mRNA expression level among different groups of ependymomas. RNA in situ hybridization (ISH) with probes specific to HOTAIR was performed on tumor tissue microarray (TMA) constructed with 19 ependymomas formalin-fixed paraffin-embedded tissue. Gene expression analysis revealed higher expression of posterior HOX genes and HOTAIR in myxopapillary ependymoma (MPE), in comparison to other spinal and intracranial ependymoma. qRT-PCR confirmed the high HOXD10 expression in spinal MPEs. There was a significant upregulation of HOTAIR expression in spinal MPE and elevated HOTAIR expressions were further confirmed by RNA ISH on the TMA. Intriguingly, HOXD10 and HOTAIR expressions were not elevated in nonependymoma spinal tumors. Our collective results suggest an important role for the lncRNA HOTAIR and posterior HOX genes in the tumorigenesis of spinal MPE. HOTAIR may also serve as a potential diagnostic marker for spinal MPE.

Background Glioma is a highly aggressive and heterogeneous cancer with poor survival rates. Homeobox (HOX) genes are transcription factors that play pivotal roles in many aspects of cellular physiology, embryonic development, and tissue homeostasis. Mutations in HOX genes can lead to increased cancer predisposition. Abnormal expression of HOXB2 may result in the development and progression of tumors. However, its prognostic value and mechanism of dysregulation remain unclear. Methods The present study included 1001 glioma patients. The correlations between the expression of HOXB2 and subgroups of glioma were investigated by t-test analyses. The prognostic value of HOXB2 was explored by Kaplan-Meier analysis as well as univariate and multivariate Cox analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were employed to detect the biological function of HOXB2 in glioma. CCK-8 and transwell assays were performed to determine the role of HOXB2 in cell proliferation and invasion. Results HOXB2 was positively correlated with tumor grade and enriched in patients with isocitrate dehydrogenase 1 wild-type and age >41 years. HOXB2 was identified as an independent prognostic biomarker in glioma patients. HOXB2 was associated with cell invasion and promoted the proliferation of glioma cells in vitro. Conclusion HOXB2 is an independent prognostic factor and contributes to tumor invasion in glioma patients.

Obligate endosymbiosis, in which distantly related species integrate to form a single replicating individual, represents a major evolutionary transition in individuality1–3. Although such transitions are thought to increase biological complexity1,2,4–6, the evolutionary and developmental steps that lead to integration remain poorly understood. Here we show that obligate endosymbiosis between the bacteria Blochmannia and the hyperdiverse ant tribe Camponotini7–11 originated and also elaborated through radical alterations in embryonic development, as compared to other insects. The Hox genes Abdominal A (abdA) and Ultrabithorax (Ubx)—which, in arthropods, normally function to differentiate abdominal and thoracic segments after they form—were rewired to also regulate germline genes early in development. Consequently, the mRNAs and proteins of these Hox genes are expressed maternally and colocalize at a subcellular level with those of germline genes in the germplasm and three novel locations in the freshly laid egg. Blochmannia bacteria then selectively regulate these mRNAs and proteins to make each of these four locations functionally distinct, creating a system of coordinates in the embryo in which each location performs a different function to integrate Blochmannia into the Camponotini. Finally, we show that the capacity to localize mRNAs and proteins to new locations in the embryo evolved before obligate endosymbiosis and was subsequently co-opted by Blochmannia and Camponotini. This pre-existing molecular capacity converged with a pre-existing ecological mutualism12,13 to facilitate both the horizontal transfer10 and developmental integration of Blochmannia into Camponotini. Therefore, the convergence of pre-existing molecular capacities and ecological interactions—as well as the rewiring of highly conserved gene networks—may be a general feature that facilitates the origin and elaboration of major transitions in individuality. Obligate endosymbiosis between the bacteria Blochmannia and ants of the Camponotini tribe originated through co-option of pre-existing molecular capacities and rewiring of developmental gene regulatory networks.

This review brings into view the prognosis attributable to glioblastoma (GBM) and resistance to treatment, surgical interventions and chemotherapy seem ineffective at procuring a better prognosis for patients with the disease. Albeit there exist varying interventions for GBM, the median survival still comes to 12 to 15 months for afflicted patients, this has aroused the need for improvement in treatment success The principal goal is to create a better prognosis and have a decline in treatment resistance invariably leading to better survival rates via adequate treatment for GBM. A relationship exists between HOX genes (homeobox genes) and glioblastoma as is evident from literature. Treatment resistance has been observed in overexpression of HOX genes, the effectiveness of treatment could result from silencing these genes A series of studies have highlighted the role that HOX genes play in glioblastoma prognosis. Promotion of human glioblastoma initiation, aggressiveness, and resistance to Temozolomide has been associated with HOXA9 as shown by Pojo et al. The role of HOX gene expression in cancer stem cells should be studied as it could provide a means of designing CSC-targeted therapies, as CSCs play a part in initiation and progression of solid tumors.

Background and Objectives: Glioblastoma is one of the most malignant and common brain tumors, accounting for about half of all gliomas. Glioblastoma is a central nervous system tumor that originates from the glial tissue of the brain. The present study aimed to investigate changes in the expression of long non-coding RNA HOXA11-AS as a possible biomarker in glioma. Methods: For the purposes of the present study, first, the medical records of the patients in Imam Hossein Hospital in Tehran, Iran were reviewed. The ethical considerations were respected as well; accordingly, written informed consent was obtained from the patients and the code of ethics was achieved as well. Finally, the paraffin blocks, including the biopsy of brain tumor tissue of the patients who referred to Imam Hossein Hospital during 2015-17 were collected and their degrees were confirmed by the pathologist. In total, 50 samples of grades 1 and 2 as well as 50 samples of grades 3 and 4 were examined in this research project. The RNA extraction and cDNA synthesis were performed for all the tissue samples donated by the patients. Subsequently, a specific primer and probe were designed and the expression of the HOXA11-AS gene was investigated using real-time polymerase chain reaction technique. The mean age of the subjects was 43.70±16.416 years. The collected data were analyzed in SPSS software (version 20) using descriptive and analytical statistics. Moreover, the expression levels of this gene in lower- and higher-grade tumor tissues were compared using the unpaired samples t-test. Results: Based on the results, the tumor samples with grade three and four underwent a 2.76 fold increase in expression (fold change), compared to tumor samples with grade one and two. This difference was statistically significant. Conclusion: Based on the findings, it can be concluded that the expression of the HOXA11-AS gene has a significant positive relationship with the degree of disease (P=0.0002).

Knowledge of the role of HOX proteins in cancer has been steadily accumulating in the last 25 years. They are encoded by 39 HOX genes arranged in 4 distinct clusters, and have unique and redundant function in all types of cancers. Many HOX genes behave as oncogenic transcriptional factors regulating multiple pathways that are critical to malignant progression in a variety of tumors. Some HOX proteins have dual roles that are tumor-site specific, displaying both oncogenic and tumor suppressor function. The focus of this review is on how HOX proteins contribute to growth or suppression of metastasis. The review will cover HOX protein function in the critical aspects of epithelial-mesenchymal transition, in cancer stem cell sustenance and in therapy resistance, manifested as distant metastasis. The emerging role of adiposity in both initiation and progression of metastasis is described. Defining the role of HOX genes in the metastatic process has identified candidates for targeted cancer therapies that may combat the metastatic process. We will discuss potential therapeutic opportunities, particularly in pathways influenced by HOX proteins.

Nucleophosmin (NPM1) mutations are encountered in myeloid neoplasia and are present in ~ 30% of de novo acute myeloid leukemia cases. This review summarizes features of mutant NPM1-related disease, with a particular emphasis on recent discoveries relevant to disease monitoring, prognostication, and therapeutic intervention. Recent studies have shown that HOX/MEIS gene overexpression is central to the survival of NPM1-mutated cells. Two distinct classes of small molecule drugs, BH3 mimetics and menin-MLL interaction inhibitors, have demonstrated exquisite leukemic cell toxicity in preclinical AML models associated with HOX/MEIS overexpression, and the former of these has shown efficacy in older treatment-naive NPM1-mutated AML patients. The results of ongoing clinical trials further investigating these compounds will be of particular importance and may alter the clinical management of patients with NPM1-mutated myeloid neoplasms. Significant scientific advancements over the last decade, including improved sequencing and disease monitoring techniques, have fostered a much deeper understanding of mutant NPM1 disease biology, prognostication, and opportunities for therapeutic intervention. These discoveries have led to the development of clinical assays that permit the detection and monitoring of mutant NPM1 and have paved the way for future investigation of targeted therapeutics using emerging cutting-edge techniques.

Hox genes of proboscipedia (pb) and Sex combs reduced (Scr) and their cofactors are required for determination of insect mouthpart identity and play important roles in insect organ morphogenesis. However, in the lepidopteran insects, including many agricultural and forest pests, the roles of these genes in determination of mouthpart morphogenesis are unclear. Here we report that both BmPB (Gene ID: 101740380) and BmSCR (Gene ID: 692761) are essential for labial palpus specification in a lepidopteran model insect, the silkworm, Bombyx mori. During embryonic morphogenesis, CRISPR/Cas9-mediated mutagenesis of BmPB induced transformation of labial palpus into thoracic leg and BmSCR mutation transformed labial palpus into maxilla. Mutagenesis of Hox-related cofactor extradenticle (BmEXD; Gene ID: 692478) and its nuclear localization factor homothorax (BmHTH; Gene ID: 576938425) also induced distortion of embryonic labial palpus. Furthermore, mutagenesis of each of the four genes induced severe degeneration of spigot morphogenesis, an important part of spinneret structure. Quantitative real-time PCR analysis further revealed that the transcriptional interaction among these genes. Our data thus provide novel evidence for Hox gene regulation of insect embryonic patterning.

Background Gastric cancer is the third leading cause of cancer-related deaths worldwide. Objective The present study aims to identify key long non-coding RNAs (lncRNAs) and their potential roles in the pathogenesis of gastric adenocarcinoma. Methods The lncRNA and mRNA expression profile between gastric adenocarcinoma and adjacent non-tumor tissues were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between gastric adenocarcinoma and adjacent non-tumor tissues were identified after bioinformatics analysis. DElncRNA-DEmRNA co-expression network and DElncRNA-nearby DEmRNA interaction network were constructed, respectively. Functional annotation for DEmRNAs interacted with DElncRNAs was performed. Receiver operating characteristic (ROC) analysis of selected DElncRNAs was conducted. Results Based on TCGA, the mRNA and lncRNA expression profiles of 375 gastric adenocarcinoma and 32 adjacent non-tumor tissues were downloaded. A total of 1502 DEmRNAs and 928 DElncRNAs between gastric adenocarcinoma and adjacent non-tumor tissues were identified. HOXC-AS3 might involve with gastric adenocarcinoma by regulating a set of HOX genes (HOXC8, HOXC9, HOXC10, HOXC11, HOXC12 and HOXC13) with cis-effect. AC115619.1-APOA4/APOB and AP006216.2-APOA1/APOA4 integrations might play roles in gastric adenocarcinoma through regulating pathways of Fat digestion and absorption and Vitamin digestion and absorption. Six lncRNAs including (HOTAIR, C20orf166-AS1, PGM5-AS1, HOXC-AS3, HOXC-AS2 and AC012531.1) have excellent diagnostic value for gastric adenocarcinoma. Conclusions This study identifies key lncRNAs in gastric adenocarcinoma which provides clues for exploring the pathogenesis and developing potential biomarkers for gastric adenocarcinoma.

Introduction. Acute lymphoblastic leukemia (ALL) is diagnosed mainly in children (2/3 of diseases) making this type of leukemia one of the most common oncological diseases among children. Oncogenes are involved in the development of ALL, in particular the product of chromosomes 1 and 19 translocation, the oncogene E2A-PBX1 that codes for E2A-PBX1 chimeric oncoprotein with strong transcription activation properties as well as oncogenes of HOX family, mainly HOXA and HOXB cluster genes. E2A-PBX1 chimeric oncoprotein and НОХА proteins are associated in vivo with factors participating in epigenetic regulation of gene expression such as chromatin modifying and remodeling enzymes that partially determines their oncogenic properties. In previous studies we obtained data indicating genetic interactions of E2A-PBX1 and НОХ genes participating in leukemia development.The aim of this research was to confirm the role of Е2А – РВХ1 oncogene in the activation of the expression of НОХА cluster genes coding for the proteins with high oncogenic potential.Materials and methods. The objects of the study were four B cell progenitor (pre-B) leukemia cell lines: RCH-ACV, KASUMI-2, 697 and NALM-6. Standard polymerase chain reaction (PCR) was used for the identification of chromosome 1 and 19 translocation product, E2A-PBX1 oncogene and its expression. Method of reverse transcription coupled with quantitative polymerase chain reaction (Q-RT-PCR) was used for the analysis of 11 HOXA cluster genes expression.Results. It is demonstrated that E2A-PBX1 oncogene is present and expressed in three studied human pre-B leukemia cell lines, RCH-ACV, KASUMI-2 and 697, while its expression is absent in NALM-6 cell line. High expression of 7 from 11 HOXА cluster genes is revealed in RCH-ACV, KASUMI-2 and 697 cell lines expressing E2A-PBX1 oncogene, whereas NALM-6 cell line, that does not express E2A-PBX1 oncogene, also does not express HOXA genes except low expression of two genes from this cluster.Conclusions. The data obtained in this study demonstrate that RCH-ACV, KASUMI-2 and 697 human leukemia pre-B cell lines, containing and expressing Е2А-РВХ1 oncogene, also express most of HOXA genes (7 genes of 11 genes) at high level in contrast to control NALM-6 cell line that does not comprise Е2А-РВХ1 oncogene and almost does not express НОХА genes. Therefore, the results of this study suggest the participation of strong transcriptional activator, chimeric oncoprotein Е2А-РВХ1, associated with chromatin modifying and remodeling enzymes, in the expression activation of HOXA cluster genes that also possess high oncogenic potential.

Animal embryogenesis is initiated by maternal factors, but zygotic genome activation (ZGA) shifts regulatory control to the embryo during blastula stages. ZGA is thought to be mediated by maternally provided transcription factors (TFs), but few such TFs have been identified in vertebrates. Here we report that NF–Y and TALE TFs bind zebrafish genomic elements associated with developmental control genes already at ZGA. In particular, co-regulation by NF–Y and TALE is associated with broadly acting genes involved in transcriptional control, while regulation by either NF–Y or TALE defines genes in specific developmental processes, such that NF–Y controls a cilia gene expression program while TALE controls expression of hox genes. We also demonstrate that NF–Y and TALE-occupied genomic elements function as enhancers during embryogenesis. We conclude that combinatorial use of NF–Y and TALE at developmental enhancers permits the establishment of distinct gene expression programs at zebrafish ZGA.

Introduction: Triple Negative Breast Cancer (TNBC) is a heterogeneous disease, clinically defined for its aggressive tumour behaviour, metastatic ability and poor prognosis. Homeobox (HOX) genes are a family of homeodomain-containing transcription factors, which establish and maintain the identity and fate of cells and tissues during normal embryogenesis and organ development. A total of 39 HOX genes exist, located in four clusters (A-D) on different chromosomes. HOX genes are dysregulated in most cancers and they have an established role in driving key processes in breast carcinogenesis, including the regulation of the cell cycle, apoptosis, angiogenesis and metastasis. In this study, we evaluated the anti-tumour efficacy of a novel inhibitor of HOX protein function, HTL-001, which antagonizes the interactions between HOX proteins and their PBX cofactors. HTL-001, developed by HOX Therapeutics Ltd, is a synthetic peptide of 18 amino acids, comprised of a hexapeptide sequence, which resembles that on HOX proteins of paralogs 1-9, and a short C-terminal polyarginine sequence for cell penetration. We evaluated the efficacy of HTL-001 in vitro as a monotherapy in all cell lines representing all molecular classifications of breast cancer and in combination with chemotherapeutics for TNBC therapy. Most importantly, HTL-001 was examined in MDA-MB-231-BR cells, which have a propensity to metastasise to the brain, reflecting the disease course frequently observed in human patients. Methods: The differential expression of HOX and PBX genes in all subtypes of breast cancer was evaluated using bioinformatics analysis of TCGA and Oncomine data. The sensitivity to HTL-001 of breast cancer-derived cell lines of different molecular classifications, was determined using Cell Proliferation (MTS) Assay and FACS-based Annexin Assay. The anti-tumour effect of HTL-001 in combination with various chemotherapeutics was assessed and analysed for synergy using Bliss Analysis. The expression of genes previously shown to respond to HOX/PBX inhibition was measured from extracted RNA and protein using RT-qPCR and western blotting, respectively. The in vivo efficacy of HTL-001 will be investigated using a mouse flank tumour xenograft model with MDA-MB-231-BR cells, representative of TNBC. Results: TCGA and Oncomine data analysis showed TNBC tumours have a unique signature of HOX gene dysregulation, different to that of all other types of breast tumours, relative to normal breast tissues; most importantly upregulation in HOXB2 and HOXB3 genes. Targeting HOX/PBX dimers with HTL-001, induced apoptotic cell death in all breast cancer cell lines including; MCF-7, ZR-75-1, MDA-MB-231, BT-20 and SK-BR-3, with the highest sensitivity seen in brain seeking MDA-MB-231-BR cells. HTL-001 significantly upregulated the expression of key apoptotic and anti-survival genes including; AIF, cFOS, and DUSP1, resulting in the induction of apoptotic cell death in all breast cancer cell lines tested. Furthermore, we observed high levels of synergy between HTL-001 and the chemotherapeutic agents, Paclitaxel, Palbociclib and 5-Fluorouracil. Conclusion: HTL-001 is a novel inhibitor of HOX and PBX protein interactions capable of marked in vitro cytotoxicity in all types of breast cancer cells, particularly in TNBC. HTL-001 induced rapid apoptosis and triggered a downstream unique signature after target engagement. HTL-001 is currently the only therapy which targets HOX gene dysregulation and in doing so, may help address the current urgent unmet therapeutic need in TNBC through its unique mechanism of action and high levels of synergy with conventional anti-cancer agents. Citation Format: Einthavy Arunachalam, Guy R Simpson, Carla Sofia Möller-Levet, Nicola Annels, Richard Morgan, Timothy Robert Crook, Hardev Singh Pandha. Therapeutic targeting of HOX gene dysregulation in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-15.

The diversity in the organization of the tracheal system is one of the drivers of insect evolutionary success; however, the genetic mechanisms responsible are yet to be elucidated. Here, we highlight the advantages of utilizing hemimetabolous insects, such as the milkweed bug Oncopeltus fasciatus , in which the final adult tracheal patterning can be directly inferred by examining its blueprint in embryos. By reporting the expression patterns, functions, and Hox gene regulation of trachealess (trh ), ventral veinless ( vvl ), and cut ( ct ), key genes involved in tracheal development, this study provides important insights. First, Hox genes function as activators, modifiers, and suppressors of trh expression, which in turn results in a difference between the thoracic and abdominal tracheal organization. Second, spiracle morphogenesis requires the input of both trh and ct , where ct is positively regulated by trh . As Hox genes regulate trh , we can now mechanistically explain the previous observations of their effects on spiracle formation. Third, the default state of vvl expression in the thorax, in the absence of Hox gene expression, features three lateral cell clusters connected to ducts. Fourth, the exocrine scent glands express vvl and are regulated by Hox genes. These results extend previous findings [Sánchez-Higueras et al., 2014], suggesting that the exocrine glands, similar to the endocrine, develop from the same primordia that give rise to the trachea. The presence of such versatile primordia in the miracrustacean ancestor could account for the similar gene networks found in the glandular and respiratory organs of both insects and crustaceans.

Species-specific traits are thought to have been acquired by natural selection. Transcription factors play central roles in the evolution of species-specific traits. Hox genes encode a set of conserved transcription factors essential for establishing the anterior-posterior body axis of animals. Changes in the expression or function of Hox genes can lead to the diversification of animal-body plans. The tunicate ascidian Ciona intestinalis Type A has an orange-colored structure at the sperm duct terminus. This orange-pigmented organ (OPO) is the characteristic that can distinguish this ascidian from other closely related species. The OPO is formed by the accumulation of orange-pigmented cells (OPCs) that are present throughout the adult body. We show that Hox13 is essential for formation of the OPO. Hox13 is expressed in the epithelium of the sperm duct and neurons surrounding the terminal openings for sperm ejection, while OPCs themselves do not express this gene. OPCs are mobile cells that can move through the body vasculature by pseudopodia, suggesting that the OPO is formed by the accumulation of OPCs guided by Hox13-positive cells. Another ascidian species, Ciona savignyi, does not have an OPO. Like Hox13 of C. intestinalis, Hox13 of C. savignyi is expressed at the terminus of its sperm duct; however, its expression domain is limited to the circular area around the openings. The genetic changes responsible for the acquisition or loss of OPO are likely to occur in the expression pattern of Hox13.

We have identified BCL6 corepressor (BCOR) as a hormone-dependent interaction partner of androgen receptor (AR), a key transcription factor in the development of normal and cancerous prostate. BCOR is often mutated in cancers and hematological diseases and as a component of a non-canonical polycomb repressive complex 1 (ncPRC1.1) required for arranging many facets of cellular differentiation. However, its role in androgen signaling or prostate cancer cells remains unknown. Here, our genome-wide analyses reveal that BCOR is recruited in an androgen-dependent fashion to majority of AR-binding chromatin sites in castration-resistant prostate cancer (CRPC) cells. Interestingly, depletion of BCOR has a significant effect on the expression of androgen-repressed genes linked to regulation of cell proliferation, differentiation and development. At many of these genes, such as HOX genes, the depletion leads to a decrease in H2A K119 monoubiquitination and an increase in mRNA expression. Consistently, BCOR depletion impairs the proliferation and viability of CRPC cells, inducing their apoptosis. Collectively, our data indicate a key role for the BCOR-ncPRC1.1 complex in the corepression of an important subset of AR target genes and the regulation of prostate cancer cell proliferation.

Homeotic or Hox genes determine the anterior-posterior body axis in all bilaterians. As expected, Hox genes are highly conserved across bilaterians. Interestingly, however, the peculiar organization of Hox genes in the form of clusters where the order of occurrence of genes in the genome corresponds to the order in which they regulate segmental identity of anterior-posterior body axis is also conserved. The relation between collinearity of arrangement of genes on the chromosomes and spatial function along the body axis has attracted attention to exploring its relevance in the precise regulation of Hox genes. Conservation of genes and their arrangement suggests a linkage between co-regulation and the higher order chromatin organization of the entire complex. To this end, we and others have used Drosophila as the model system to understand the cis-and trans-regulatory components of Hox genes. A number of chromatin-level regulatory elements, like chromatin domain boundaries, and Polycomb Response Elements (PREs) have been discovered in this process. Interestingly, much of what has emerged from the study of homeotic genes, the cis-elements and protein factors, have relevance across the genome in a large number of regulatory events beyond the Hox genes. Here, we review our findings and discuss their genome-wide implications in complex regulatory processes.

Abstract: HOX transcript antisense intergenic RNA (HOTAIR) is one of the most studied long noncoding RNAs (lncRNAs) and is aberrantly expressed in colorectal cancer (CRC). We thus performed a comprehensive study based on meta-analysis and validation of the TCGA database to investigate clinicopathological and prognostic value of HOTAIR in CRC. Six studies enrolling 629 CRC patients were included in the analysis. The results indicated that high HOTAIR expression predicted worse OS (hazard ratio [HR] = 2.46, 95% confidence interval [CI]: 1.82-3.32, P < 0.01) and RFS (HR = 1.97, 95% CI: 1.27-3.05, P < 0.01) for CRC patients. High HOTAIR expression was also significantly associated with venous invasion (OR = 2.53, 95% CI: 1.12-5.68, P = 0.02), advanced tumor infiltration (OR = 3.35, 95% CI: 1.34-8.42, P = 0.01) and distant metastasis (OR = 5.52, 95% CI: 1.22-25.01, P = 0.03). Then, the results were validated by the TCGA database, showing that the up-regulated expression of HOTAIR was significantly related to poor OS (P = 0.01) and RFS (P = 0.04) in CRC. Our meta-analysis indicated that high HOTAIR expression was closely associated with poor clinical outcomes and could be a reliable prognostic biomarker for CRC patients.

The expression and function of hox genes have played a key role in the debate on the evolution of limbs from fins. As an early branching tetrapod lineage, lissamphibians may provide information on the origin of the limb's hox domains and particularly how the plesiomorphic tetrapod pattern compares to the hox pattern present in fish fins. Here, we comparatively investigated the expression of hox genes in the developing limbs of axolotl and Xenopus laevis as well as in the fins of the direct developing cichlid Astatotilapia burtoni. In contrast to axolotl, which has only very low digital expression of hoxd11, Xenopus limbs recapitulate the reverse collinear hoxd expression pattern known from amniotes with clearly defined proximal and distal hoxd11 expression domains. For hoxa genes, we observe that in Xenopus limbs, as in axolotl, a clear distal domain of hoxa11 expression is present, although in the presence of a hoxa11 antisense transcript. Investigation of fins reveals the presence of hoxa11 antisense transcription in the developing fin rays in a domain similar to that of hoxa13 and overlapping with hoxa11 sense transcription. Our results indicate that full exclusion of hoxa11 from the autopod only became firmly established in amniotes. The distal antisense transcription of hoxa11, however, appears to predate the evolution of the limb, but likely originated without the concurrent implementation of the transcriptional suppression mechanism that causes mutually exclusive hoxa11 and hoxa13 domains in amniotes.

Evolutionary developmental biology (evo-devo) formed due to the interactions of evolutionary biology, paleontology, and comparative genomics, analyzes the interrelations of ontogenetic and phylogenetic processes and, primarily, the influence of changes in individual development are under genetic control, and Hox genes play a decisive role in the determination of animal’s body plan. Both genetic and epigenetic mechanisms underlie the regulation of body plan formation in ontogeny and phylogeny, and the latter mechanisms ultimately determine the animal’s phenotype. Heterochronies, which create the differences between related taxa (species and genus), play an important role in the evolutionary transformations. Data from paleontology, evolutionary biology, and genomics enabled the construction of a phylogenetic system that includes the time of divergence of evolutionary branches of different ranks, in addition to the evolutionary innovations.

The problem of vertebrate head metamerism was first posed more than 200 years ago. This issue gave rise to two approaches: segmentalism, which relies on the model of the typical head segment, and antisegmentalism, which rejects the existence of cephalic segments altogether. The truth, probably, lies somewhere in the middle. Data on the development of the head mesoderm, cranial neural crest, and cranial nerves lead to the conclusion that there are five metameres in the vertebrate head: premandibular, mandibular, hyoid, 1st metahyoid, and 2nd metahyoid. According to the hypothesis of F. Edgeworth, this number of head metameres is primary; the head spreading back occurred as a result of the polymerization of visceral arches inside the nervus vagus metamere which had originally included only the 2nd metahyoid arch. According to the hypothesis of C. Gegenbaur, initially, the visceral arches were more numerous in this area and the branchial nerves merged into a single nervus vagus system only secondarily. The Cambrian paleontology may assist in resolving this controversy. In any case, vertebrate head metamerism is primarily heteronomous (as interpreted by P.P. Ivanov): the premandibular and mandibular metameres are morphologically atypical and lie beyond the Hox gene expression zone. Developmental biology shows that the bodies of other metameric animals are arranged on the basis of similar principles.

HOX genes are a group of evolutionarily conserved genes that encode a family of transcription factors that regulate early developmental morphogenetic processes and continue to be expressed into adulthood. These highly conserved HOX factors play an unquestioned crucial role as master regulators during embryonic vertebrate development and morphogenesis by controlling the three dimensional body plan organization. HOX genes specify regions of the body plan of an embryo along the head-tail axis. They encode proteins that specify the characteristics of ‘position’, ensuring that the correct structures form in the correct places of the body. Expression of HOX is known to persist in many tissues in the postnatal period suggesting the role of these genes not only during development but also for the functioning of tissues throughout life. The tissue-specific pattern of HOX gene expression is inherent in stromal/stem cells of mesenchymal origin, such as mesenchymal stromal cells, fibroblasts, smooth muscle cells, and preadipocytes, enabling them to memorize their topographic location in the form of their HOX code and to fulfill their location-specific functions. In this chapter, we focus on the expression and potential role of HOX genes in adult tissues. We review evidence that site-specific expression of HOX genes is connected to location-specific disease susceptibility and review studies showing that dysregulated expression of HOX genes can be associated with various diseases. By recognizing the importance of site-specific molecular mechanisms in the organ stroma, we gain new insights into the processes underlying the site-specific manifestation of disease.

Species retaining ancestral features, such as species called living fossils, are often regarded as less derived than their sister groups, but such discussions are usually based on qualitative enumeration of conserved traits. This approach creates a major barrier, especially when quantifying the degree of phenotypic evolution or degree of derivedness, since it focuses only on commonly shared traits, and newly acquired or lost traits are often overlooked. To provide a potential solution to this problem, especially for inter-species comparison of gene expression profiles, we propose a new method named “derivedness index” to quantify the degree of derivedness. In contrast to the conservation-based approach, which deals with expressions of commonly shared genes among species being compared, the derivedness index also considers those that were potentially lost or duplicated during evolution. By applying our method, we found that the gene expression profiles of penta-radial phases in echinoderm tended to be more highly derived than those of the bilateral phase. However, our results suggest that echinoderms may not have experienced much larger modifications to their developmental systems than chordates, at least at the transcriptomic level. In vertebrates, we found that the mid-embryonic and organogenesis stages were generally less derived than the earlier or later stages, indicating that the conserved phylotypic period is also less derived. We also found genes that potentially explain less derivedness, such as Hox genes. Finally, we highlight technical concerns that may influence the measured transcriptomic derivedness, such as read depth and library preparation protocols, for further improvement of our method through future studies. We anticipate that this index will serve as a quantitative guide in the search for constrained developmental phases or processes.

Description, Full replacement of D. melanogaster pb Hox locus with D. mimica pb locus produces mouthparts with similarities to D. mimica., Hox genes determine positional codes along the head-to-tail axis. Here, we replaced the entire Drosophila melanogaster proboscipedia (pb) Hox locus, which controls the development of the proboscis and maxillary palps, with that from Drosophila mimica, a related species with highly modified mouthparts. The D. mimica replacement rescues most aspects of adult proboscis morphology; however, the shape and orientation of maxillary palps were modified, resembling D. mimica and closely related species. Expressing the D. mimica Pb protein in the D. melanogaster pattern fully rescued D. melanogaster morphology. However, the expression pattern directed by D. mimica pb cis-regulatory sequences differed from that of D. melanogaster pb in cells that produce altered maxillary structures, indicating that pb regulatory sequences can evolve in related species to alter morphology.

In this study, we have identified the entire complement of typical homeobox (Hox) genes (Lab, Pb, Dfd, Scr, Antp, Ubx, Abd-A, and Abd-B) in harpacticoid and calanoid copepods and compared them with the cyclopoid copepod Paracyclopina nana. The harpacticoid copepods Tigriopus japonicus and Tigriopus kingsejongensis have seven Hox genes (Lab, Dfd, Scr, Antp, Ubx, Abd-A, and Abd-B) and the Pb and Ftz genes are also present in the cyclopoid copepod P. nana. In the Hox gene cluster of the calanoid copepod Eurytemora affinis, all the Hox genes were present linearly in the genome but the Antp gene was duplicated. Of the three representative copepods, the P. nana Hox gene cluster was the most compact due to its small genome size. The Hox gene expression profile patterns in the three representative copepods were stage-specific. The Lab, Dfd, Scr, Pb, Ftz, and Hox3 genes showed a high expression in early developmental stages but Antp, Ubx, Abd-A, and Abd-B genes were mostly expressed in later developmental stages, implying that these Hox genes may be closely associated with the development of segment identity during early development.

How organs achieve their final shape is a problem at the interface between physics and developmental biology. Organs often involve multiple interacting tissue layers that must be coordinated to orchestrate the complex shape changes of development. Intense study uncovered genetic, and physical ingredients driving the form of mono layer tissue. Yet, tracing dynamics across tissue layers, and scales – from cell to tissue, to entire organs – remains an outstanding challenge. Here, we study the midgut ofDrosophilaembryos as a model visceral organ, to reconstructin totothe dynamics of multi-layer organ formationin vivo. Using light-sheet microscopy, genetics, computer vision, and tissue cartography, we extract individual tissue layers to map the time course of shape across scales from cells to organ. We identify the kinematic mechanism driving the shape change due to tissue layer interactions by linking out-of-plane motion to active contraction patterns, revealing a convergent extension process in which cells deform as they flow into deepening folds. Acute perturbations of contractility in the muscle layer using non-neuronal optogenetics reveals that these contraction patterns are due to muscle activity, which induces cell shape changes in the adjacent endoderm layer. This induction cascade relies on high frequency calcium pulses in the muscle layer, under the control of hox genes. Inhibition of targets of calcium involved in myosin phosphorylation abolishes constrictions. Our study of multi-layer organogenesis reveals how genetic patterning in one layer triggers a dynamic molecular mechanism to control a physical process in the adjacent layer, to orchestrate whole-organ shape change.

The highly conserved homology cassette family (HOX) as well as 18 referenced long non-coding antisense transcripts (HOXATs) play vital roles in the development of some cancers. Nevertheless, their expression patterns as well as their association with cancer prognosis and the tumor microenvironment (TME) in pan-cancers are still unclear. Here, based on public databases, the expression levels of HOXATs, their prognostic potentials, and correlation with tumor mutation burden (TMB), immune cell infiltration, immune subtype, immune response-related genes, and stemness scores corresponding to 33 tumor types were analyzed systematically using R language. The results of the analysis indicated that different cancer tissues show different HOXAT expression profiles. Further, HOXAT expression showed association with cancer prognosis and immune and stemness regulation. Gene set enrichment analysis also demonstrated that HOXATs participate in cancer- and immune-related pathways, and based on their expression levels, HOTAIRM1 and HOXB-AS1 showed potential involvement in oncogenesis as well as possible involvement in immune regulation across a variety of cancer types. Further investigation also confirmed a significantly higher expression of HOXB-AS1 in GBM than in lower grade glioma tissues. Importantly, in vitro cell function experiments indicated that HOXB-AS1 supports cancer stem cell and plays a fundamental role in glioma metastasis. In conclusion, our results provide valuable resources that can guide the investigation of the mechanisms related to the role of HOXATs in cancers as well as therapeutic analysis in this regard.